Sepsis remains a serious clinical problem causing thousands of deaths each year. Therapy for the treatment of sepsis has not progressed due to the lack of understanding of the basic inflammatory processes. The previous prevailing hypothesis postulated that patients with sepsis have too much inflammation, therefore blocking inflammatory mediators would decrease organ injury and death. As information was gathered it became clear that this hypothesis represented an oversimplification of the complex inflammatory events. This application will study two hypotheses using the clinically relevant murine model of sepsis induced by cecal ligation and puncture (CLP). The first hypothesis states that deaths during the first days after CLP are due to an exaggerated immune response and will be tested by three specific aims. The first specific aim will block inflammatory mediators to improve survival. This serves as more than just an extension of previously failed clinical trials since we will attempt combination immunotherapy. The second specific aim will tailor the anti- inflammatory therapy based on the individual response. Rather than providing exactly the same therapy to each animal, the therapy will be directed by rapidly measuring the level of inflammation and providing the appropriate therapy. The third specific aim will attempt to improve outcome by increasing neutrophil recruitment to the site of inflammation, the peritoneum. While neutrophils may cause organ injury, they are also a critical component of the innate immune response for the control of the invading bacteria. Our second hypothesis states that deaths which occur beyond the first few days post CLP are the result of the immunosuppressed state of the animal. The fourth specific aim will test this hypothesis by providing exogenous cytokines such as tumor necrosis factor and interleukin one. These exogenous cytokines will be given systemically in an attempt to boost the immune response of the animal. In our last specific aim we will evaluate trauma patients by carefully measuring plasma levels of cytokines over time. This will be coupled with determining the ability of whole blood from these patients to be stimulated to produce cytokines. Successful completion of our studies will provide the basic knowledge about inflammatory response in sepsis, knowledge needed to reduce the impact of sepsis.